The process of aging is associated with irreversible physiological changes to the circulatory system, leading to an increased risk of blood pressure disorders, Coronary Heart Disease (CHD), and stroke. For women, this risk rises dramatically after the onset of menopause. These conditions have a significant impact on quality of life for the middle-aged and elderly and account for a large proportion of deaths and chronic illnesses in modern societies.
Patients suffering from cardiovascular disorders are frequently prescribed anticoagulants, antihypertensives, cholesterol-lowering medications, and the like. These medications usually present harmful side-effects or health risks, and moreover, the chronic effects of taking such medication regularly over the course of years or decades are not well studied. As life expectancies increase, it would be desirable to find long-term, safe and reliable natural therapies to prevent, treat or even reverse the consequences of aging on the vasculature.
Changes in mechanical properties of the main arteries have major implications for the development of vascular disease. Arteries, especially the larger elastic arteries such as the common carotid artery, become stiffer with age. Peak elasticities are achieved at about age 14-15, after which they deteriorate gradually. Measures of large artery stiffening include compliance and distensibility. Compliance reflects the buffering capacity of the vascular vessel wall, and distensibility refers to the intrinsic vascular wall elasticity. In cross-sectional studies it has been shown that the distensibility and compliance of the elastic common carotid artery decrease linearly with age. The increase in arterial stiffness with increasing age is suggested to occur more rapidly in women aged between 45 and 60 years than in men of the same age group due to the lack of oestrogen after menopause.
Reductions in compliance and distensibility result in an impairment of the arterial system to cushion pulsatile pressure. Arterial stiffening results in a higher pulse wave velocity and earlier wave reflections. This increases systolic and pulse pressure and consequently cardiac workload. To compensate, the arterial diameter increases with age. Over time, arterial stiffening can contribute to the development of inter alia left ventricular hypertrophy, congestive heart failure and coronary heart disease.
It has long been recognized that vitamin K is an essential component of the diet. It was first identified as an element needed to prevent haemorrhaging by activating blood-clotting factors. Natural K-vitamers are menadione-derivatives differing from each other in the polyisoprenoid side chain attached to the 3-position of the ring structure. Vitamin K can be provided in the diet by dark green, leafy vegetables (K1 or phylloquinone), and by fermented foods such as cheese and curd (K2 or menaquinone). K2 vitamins are also synthesized in the small intestine by resident symbiotic bacteria. Vitamin K is also needed for carboxylation of two bone matrix proteins necessary for normal bone metabolism.
In EP-A-0 679 394 and likewise in Jpn. J. Pharmacol. (1997) 75:135-143 it is disclosed that a high dietary intake of vitamin K and related molecules can reduce further arterial calcification, but not reverse it, from which it is concluded that arteriosclerosis can be treated using vitamin K. Arteriosclerosis is a disease of the arteries characterized by inflammation, macrophage invasion, foam cell formation, intima thickening, accretion of cholesterol, and formation of an atherosclerotic plaque, which over time can become calcified. The onset of atherosclerosis is invariably in the large arteries such as for example, the aorta and coronary arteries. In more advanced stages one may see plaque rupture leading to sudden vascular occlusion, myocardial infarction and cerebrovascular accident (infarction of the brain).
A completely different process is that of vascular stiffening due to loss of elasticity of the arteries. Vascular stiffening is associated with ageing, diabetes mellitus and renal dysfunction; it is the result of degradation of the elastic lamellae in the tunica media resulting in loss of elasticity. The onset of vascular stiffening is generally seen in the smaller vessels, but extends to the larger arteries. This will lead to increased blood pressure, vascular widening, and in later stages to rupture of (mainly the small) arteries and capillaries.
Studies have shown that also on a molecular level age-related stiffening of the arteries can be distinguished from arteriosclerotic/atherosclerotic calcification. Whereas atherosclerosis is invariably associated with inflammation and starts with destruction of the endothelial cell layer at the luminal side of the tunica intima, age-related stiffening is a process, which originates in the tunica media, and is not associated with inflammation. It is believed that age-related stiffening occurs as a result of deposition of minerals around the elastic fibres of the tunica media, followed by degradation of the elastin structure. After deterioration of the elastin, the elastic properties of the artery depend on collagen, which is much less flexible.
There is a need for effective compositions and methods for preventing and treating cardiovascular disease. Compositions and methods that can reduce or reverse abnormal calcification of blood vessels are especially needed.